Continuous asymmetric Michael addition of ketones to β-nitroolefins(1R,2R)-(+)-1,2-DPEN-modified sulfonic acid resin

Article abstract of DOI:10.1039/c4cy00936c

A trifunctional catalyst was successfully prepared by bonding (1R,2R)-(+)-1,2-DPEN to sulfonic acid resin. The catalyst was characterized by elemental analysis, thermogravimetric (TG) analysis and infrared (IR) spectroscopy. The results indicated the coex

Full text of DOI:10.1039/c4cy00936c

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Continuous asymmetric Michael addition of
ketones to β-nitroolefins over IJ1R,2R)-IJ+)-1,2-
DPEN-modified sulfonic acid resin†
Cite this: Catal. Sci. Technol., 2015,
5, 724
ab
Jun Tian,ab Chao Zhang,a Xuefei Qi,a Xilong Yan,ab Yang Liab and Ligong Chen
*
A trifunctional catalyst was successfully prepared by bonding IJ1R,2R)-IJ+)-1,2-DPEN to sulfonic acid resin.
The catalyst was characterized by elemental analysis, thermogravimetric (TG) analysis and infrared (IR)
spectroscopy. The results indicated the coexistence of sulfonic, sulfonamido and primary amino groups
on the surface of the resin. Based on the IR spectroscopy of the catalyst treated with a solution of acetone
and β-nitrostyrene in toluene, the catalytic mechanisms were proposed. It was found that these
three groups had a synergistic effect. Subsequently, the continuous Michael addition of acetone to
β-nitrostyrene was achieved in a fixed-bed reactor over this catalyst and the reaction parameters were
optimized. Under the optimized conditions moderate β-nitrostyrene conversion (65.5%) and excellent
enantioselectivity (93.0%) were obtained. Finally, the generality of the catalyst was evaluated with the
Michael addition of aldehydes or ketones to β-nitroolefins, and the catalyst exhibited moderate to excellent
enantioselectivity (81.6% to 99.0% ee) except for the addition of isobutylaldehyde to β-nitrostyrene.
Received 17th July 2014,
Accepted 10th September 2014
DOI: 10.1039/c4cy00936c
www.rsc.org/catalysis
It is obvious that chiral compounds play crucial roles in
biological processes. Asymmetric Michael addition of
ketones (aldehydes) to nitroolefins is one of the most
versatile methods for the construction of chiral compounds
and thus attracts tremendous attention.1 As early as 2001,
List et al.2 reported the enantioselective Michael addition of
cyclohexanone to β-nitrostyrene catalyzed by L-proline. Since
then, this reaction has always been taken as a model, and
organocatalysts that are more efficient for this model keep
emerging.3 However, most of them presented poor catalytic
performance for the Michael addition of acetone to nitro-
styrene. Now, acetone is still a problematic substrate for the
nitro-Michael addition.4 In order to enhance the enantio-
selectivity and the yield, some studies have recently focused
on the design of catalysts. Terakado et al.5 employed
(S)-homoproline hydrochloride as a catalyst for this Michael
addition with less than 50% ee. Vijaikumar et al.6 studied
this asymmetric Michael addition in the presence of L-proline
anchored on hydrotalcite clays with only 14% ee. Obviously,
chiral proline derivatives displayed poor enantioselectivity for
this reaction. Moreover, based on the chiral diamine
skeletons, especially 1,2-diphenylethane-1,2-diamine7 and
cyclohexane-1,2-diamine,8 thiophosphoramides,9 sulfamides10
and thioureas11 were synthesized and evaluated for the
asymmetric Michael addition of acetone to nitrostyrene. All
of them exhibited satisfactory enantioselectivity, but separa-
tion from the reaction mixture and recycling are difficult.
Portnoy et al.12 immobilized the chiral diamine on dendronized
Wang PS resin. Although sufficient yields and stereo-
selectivities were achieved, certain drawbacks still existed,
such as complicated multi-step synthesis and requirement
of acidic additives. Besides, the aforementioned operations
were all carried out in flasks and the continuous asymmetric
Michael additions were rarely touched.
In this paper, IJ1R,2R)-IJ+)-1,2-diphenylethylenediamine
[(1R,2R)-(+)-1,2-DPEN] was selected and bonded to sulfonic
acid resin by simple N-sulfonyl reaction (Fig. 1). Then, the
continuous asymmetric Michael addition of acetone to
β-nitrostyrene in a fixed-bed reactor was realized over the
obtained (1R,2R)-(+)-1,2-DPEN-modified resin without any
additives. The catalyst was characterized by elemental and
TG analyses and IR spectroscopy to clarify the coexistence of
sulfonic, sulfonamido and primary amino groups on the
surface of the resin. Meanwhile, the catalyst was treated with
a solution of acetone and β-nitrostyrene in toluene and then
characterized by IR to investigate the catalytic mechanism.
Finally, the reaction conditions were optimized and the
a School of Chemical Engineering and Technology, Tianjin University, Tianjin
300072, PR China. E-mail: lgchen@tju.edu.cn; Fax: +86 022 27406314;
Tel: +86 022 27406314
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300072, PR China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cy00936c
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Fig. 1 The modification of sulfonic acid resin with IJ1R,2R)-IJ+)-1,2-DPEN.
generality of the catalyst was investigated under the opti-
mized reaction conditions.
Results and discussion
As an effective catalyst for Michael addition of acetone to
β-nitrostyrene, the amide group is required as a hydrogen
bond donor apart from the primary amino group, ensuring
the ability to form an enamine or imine.11,13 In addition,
acidic additives, such as hydrochloric acid,5 sulfonic acid,4b,14
carboxylic acid4a,15and even phenol,9a are necessary to accel-
erate the reaction.9b,12a In fact, the amide groups, the primary
amino groups and the acidic additives played a synergistic
effect on this asymmetric Michael addition. Therefore, in this
paper, IJ1R,2R)-IJ+)-1,2-DPEN was selected and linked to
sulfonic acid resin through a sulfamide bond. The formation
of sulfamide bond favored the strengthening of the hydrogen
bonding with β-nitrostyrene, and the sulfonic group derived
from the hydrolysis of sulfonyl chloride served as acidic
additive. The Michael addition of acetone to β-nitrostyrene
was carried out over (1R,2R)-(+)-1,2-DPEN-modified sulfonic
acid resin in a fixed-bed reactor with moderate conversion
and excellent enantioselectivity. The satisfactory reactivity
might be attributed to the synergistic effect of sulfonic,
sulfonamido and primary amino groups on the surface of
the resin. In order to confirm the coexistence of these three
functional groups, the catalyst was characterized by elemen-
tal and TG analyses and IR spectroscopy.
Fig. 2 TG and DTG profiles of IJ1R,2R)-IJ+)-1,2-DPEN-modified sulfonic
acid resin.
The FTIR spectra of IJ1R,2R)-IJ+)-1,2-DPEN-modified sul-
fonic acid resin, (1R,2R)-(+)-1,2-DPEN and (1R,2R)-(+)1,2-
DPEN-modified sulfonic acid resin treated with acetone and
β-nitrostyrene are shown in Fig. 3a, b and c, respectively. As
shown in Fig. 3, all of them displayed a peak at 3437 cm−1
belonging to the O–H stretching vibration of H2O. In addi-
tion, the absorption peaks occurring at 1324 cm−1 and
1153 cm−1 (Fig. 3a) could be ascribed to the SO asymmetric
and symmetric stretching vibrations, respectively.16 The peak
around 1059 cm−1 corresponded to the N–SO2 stretching
vibration,17 and another peak at 1537 cm−1 to the N–H
bending vibration of sulfamide.18 The presence of these four
peaks confirmed that (1R,2R)-(+)-1,2-DPEN has been
anchored on the surface of the resin by sulfamide bond.
Meanwhile, the peak at 515 cm−1 was assigned to the absorp-
tion of the SO3–H group19 and the peak at 3367 cm−1 was the
N–H stretching vibration of the amino group. Thus, a conclu-
sion could be made that sulfonic, sulfonamido and primary
amino groups coexisted on the surface of the resin.
The sulfur and nitrogen contents of IJ1R,2R)-IJ+)-1,2-DPEN-
modified sulfonic acid resin were determined by elemental
analysis. The results indicated that each gram of the cata-
lyst contained 1.87 mmol of nitrogen and 1.99 mmol of
sulfur. The sulfur content was lower than that of sulfonyl
chloride resin (2.35 mmol g−1), which was attributed to the
introduction of (1R,2R)-(+)-1,2-DPEN. Meanwhile, 1.87 mmol g−1
of nitrogen content implied that about half of the sulfonyl
chloride was consumed by (1R,2R)-(+)-1,2-DPEN to form
sulfamide and the rest would be hydrolyzed into sulfonic
acid in the catalyst post-processing. The TG and DTG
profiles of the catalyst are shown in Fig. 2. The TG profile
indicated that with the increase in temperature from 30 to
800 °C, there were two distinct weight losses in the ranges of
30–100 °C and 220–470 °C, corresponding to the desorption
of absorbed water and the degradation of the catalyst, respec-
tively. The DGT profile displayed three peaks in the range of
220–470 °C, which were possibly attributed to three stages of
the catalyst degradation: the breakage of the sulfamide bond,
desulfonation and the collapse of the resin skeleton. It was
consistent with the results of the elemental analysis.
In order to understand this catalytic reaction, the catalyst
was immersed into a solution of acetone (1.33 mol L−1) and
β-nitrostyrene (0.133 mol L−1) in 20 mL of toluene for 48 h at
Fig. 3 The infrared spectra of IJ1R,2R)-IJ+)-1,2-DPEN-modified sulfonic
acid resin (a), (1R,2R)-(+)-1,2-DPEN (b), and (1R,2R)-(+)-1,2-DPEN-
modified sulfonic acid resin treated with acetone and β-nitrostyrene (c).
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Table 1 The influence of temperature on the addition of acetone to
β-nitrostyrenea
ambient temperature and then characterized by FT-IR. The
results are shown in Fig. 3c. Obviously, the peak of the N–H
stretching vibration of the amino group disappeared and this
might be attributed to the formation of imine or enamine
intermediate with acetone. Moreover, the N–H bending vibra-
tion of sulfamide has an upshift of 5 cm−1 for the hydrogen
bond between sulfamide and β-nitrostyrene.
Temperature/°C
Conversionc/%
eeb,c/%
25
35
45
65.5
77.6
78.3
93.0
75.7
74.9
a
Reaction conditions: solution of 1.33 mmol of acetone and
On the basis of the IR analysis, combined with the results
reported by Lin et al.10 and Lital et al.,12a the catalytic mecha-
nism was proposed as shown in Fig. 4. IJ1R,2R)-IJ+)-1,2-DPEN-
modified sulfonic acid resin behaved as a trifunctional
catalyst. First, acetone was activated via protonation or the
hydrogen bonding interaction with the sulfonic acid group.
The nucleophilic addition and the following dehydration
yielded imine intermediate 1.10,12a In addition, the hydrogen
bonding between the sulfonamido group and the nitro group
enhances the electrophilicity of β-nitrostyrene and the
enantioselectivity. Subsequently, the imine intermediate 1
was balanced with the enamine intermediate, which attacked
the activated β-nitrostyrene to form the highly enantio-
selective imine intermediate 2. It was easily transformed
into the Michael adduct by nucleophilic addition of H2O and
the subsequent deamination with the aid of sulfonic acid.
It was obvious that the sulfonic group favored the activation
of acetone and the release of the Michael adduct. Impor-
tantly, sulfonic, sulfonamido and primary amino groups
played a synergistic role on the formation of the target
compound. In order to further confirm the catalytic mecha-
nism and improve the reaction, the effects of temperature,
acetone/β-nitrostyrene molar ratio and solvents on the Michael
addition of acetone to β-nitrostyrene were investigated.
0.133 mmol of β-nitrostyrene in 20 mL of toluene; charging rate:
b
0.6 mL h−1
.
The results were determined by HPLC using an AS
column. c The conversion was obtained by HPLC using an AS column
and each data point is a median of three consecutive and similar
analytical results.
that the elevated temperature favored Michael addition of
acetone to β-nitrostyrene. However, as the temperature
increased, the proportion of protonated acetone that directly
attacked β-nitrostyrene to generate the raceme was enhanced
(Fig. 5), which may be the main reason for the decrease in
the enantioselectivity.
Table 2 clearly indicated that with the increase in acetone/
β-nitrostyrene molar ratio from 10 : 1 to 25 : 1, the conversion
of β-nitrostyrene essentially remained unchanged due to the
supersaturation of active sites of the catalyst. Meanwhile, the
enantioselectivity dramatically decreased from 93.0% to
76.5%. It was not hard to understand that the excess acetone
would lead to the increase in the mixed solvent polarity.
It possibly weakened the hydrogen bonding between
β-nitrostyrene and the amino group of sulfamide, resulting in
the decreased enantioselectivity of the Michael adduct. There-
fore, the effects of solvent polarity on the catalytic activity
and enantioselectivity were subsequently investigated.
Table 3 revealed that solvents presented a significant
effect on the conversion of β-nitrostyrene and the enantio-
selectivity of the adduct. Polar solvents such as methanol,
acetone, acetonitrile and tetrahydrofuran resulted in moder-
ate to good β-nitrostyrene conversion (55.1–99.6%) and
poor enantioselectivity (38.7–58.4%). By contrast, nonpolar or
weak polar solvents such as toluene, dichloromethane,
chloroform and tetrachloromethane gave poor to moderate
β-nitrostyrene conversion (31.6–65.5%) and better enantio-
selectivity (82.4–93.0%). Obviously, toluene was the most
suitable solvent for the Michael addition of acetone to
β-nitrostyrene with respect to the β-nitrostyrene conversion
and the enantioselectivity of the Michael adduct. As men-
tioned above, the hydrogen bonding with β-nitrostyrene
was also crucial to improve the enantioselectivity. However,
polar solvents always weakened or retarded the formation of
hydrogen bonds between β-nitrostyrene and the amino group
Initially, the influence of temperature on the asymmetric
Michael addition of acetone to β-nitrostyrene was investi-
gated and the results are shown in Table 1. It was found
that with the increase in temperature from 25 to 45 °C,
the conversion of β-nitrostyrene increased from 65.5%
to 78.3%, whereas the enantioselectivity of the Michael
adduct decreased from 93.0% to 74.9%. There is no doubt
Fig.
4
The mechanism of the Michael addition of acetone to
Fig. 5 The Michael addition of acetone to β-nitrostyrene catalyzed by
β-nitrostyrene over IJ1R,2R)-IJ+)-1,2-DPEN-modified sulfonic acid resin.
sulfonic acid.
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Table 2 The influence of molar ratio on the addition of acetone to
β-nitrostyrenea
Table 4 Asymmetric Michael addition of aldehydes or ketones to
nitroolefinsa
Molar ratiob
Conversiond/%
eec,d/%
10 : 1
15 : 1
20 : 1
25 : 1
65.5
65.0
65.3
65.6
93.0
84.2
82.8
76.5
R1, R2, R3
R4
Conversionc/% eeb,c/% drd (syn/anti)
CH3–, H–, H– Ph–
CH3–, H–, H– 4-Cl–Ph–
CH3–, H–, H– 2-Cl–Ph–
CH3–, H–, H– 4-MeO–Ph– 47.1
–IJCH2)4–
–IJCH2)3–
Et–, Me–, H– Ph–
H–, Et–,H– Ph–
H–, Me–,Me– Ph–
65.5
95.7
90.9
93.0
92.8
96.7
94.9
94.5
85.2
81.6
—
—
—
—
93 : 7
98 : 2e
>99 : 1
a
Reaction conditions: solution of 0.133 mmol of β-nitrostyrene in
20 mL of toluene; charging rate: 0.6 mL h−1; temperature: 25 °C.
b
c
The molar ratio of acetone and β-nitrostyrene. The results were
d
Ph–
Ph–
95.5
29.7
16.3
98.7
Trace
determined by HPLC using an AS column. The conversion was
obtained by HPLC using an AS column and each data point is a
median of three consecutive and similar analytical results.
>99.0% >99 : 1
—
—
a
Reaction conditions: solution of 1.33 mmol of ketones and
0.133 mmol of nitroolefins in 20 mL of toluene; charging rate:
Table 3 The influence of solvents on the addition of acetone to
β-nitrostyrenea
b
0.6 mL h−1; temperature: 25 °C. The results were determined by
c
HPLC using an AS column. The conversion was obtained by HPLC
Solvents
Conversionc/%
eeb,c/%
using an AS column and each data point is a median of three
d
consecutive and similar analytical results. The dr value was
Toluene
DCM
CHCl3
CCl4
65.5
44.4
34.1
31.6
96.5
55.1
88.7
99.6
93.0
88.3
82.4
91.8
38.7
57.2
49.5
58.4
e
determined by HPLC apart from the adduct of cyclopentanone. The
dr value was determined by 1H NMR of the crude product.
THF
CH3CN
Acetone
CH3OH
3-pentanone exhibited lower β-nitrostyrene conversion
and enantioselectivity. In addition, only traces of the Michael
adducts of isobutylaldehyde were detected. The poor reac-
tivity and enantioselectivity were mainly attributed to the
steric hindrance which restricted the formation of the
imine intermediate.
a
Reaction conditions: solution of 1.33 mmol of acetone and
0.133 mmol of β-nitrostyrene in 20 mL of toluene; charging rate:
b
0.6 mL h−1; temperature: 25 °C. The results were determined by
c
HPLC using an AS column. The conversion was obtained by HPLC
using an AS column and each data point is a median of three con-
secutive and similar analytical results.
Conclusion
A trifunctional catalyst was successfully prepared by simple
N-sulfonylation of (1R,2R)-(+)-(1,2)-DPEN with sulfonyl
chloride resin. The catalyst was characterized by elemental
and TG analyses and IR spectroscopy. The results indicated
the coexistence of sulfonic, sulfonamido and primary amino
groups on the surface of the resin. Furthermore, the catalyst
was treated with the solution of acetone and β-nitrostyrene in
toluene and then characterized by IR spectroscopy. Based on
the IR analysis, the catalytic mechanism was proposed. It was
found that sulfonic, sulfonamido and primary amino groups
possibly had a synergistic effect on the conversions of
β-nitrostyrene and the enantioselectivities of the Michael
adduct. The catalyst was employed for the continuous
Michael addition of acetone to β-nitrostyrene in a fixed-bed
reactor and the reaction parameters were optimized. Under
the optimized conditions moderate β-nitrostyrene conver-
sion (65.5%) and excellent enantioselectivity (93.0%) were
obtained. Finally, the generality of the catalyst was investi-
gated with the Michael addition of aldehydes or ketones to
nitroolefins. The catalyst exhibited moderate to excellent
enantioselectivity (81.6% to 99.0% ee) except for the Michael
addition of isobutylaldehyde to β-nitrostyrene. The reason
might be attributed to the steric hindrance which restricted
the formation of the imine intermediate.
of sulfamide; thus, the enantioselectivity decreased. Besides,
the ionization of sulfonic acid was also promoted by polar
solvents. β-Nitrostyrene was activated by protonation and
then reacted with the enamine intermediate to yield raceme.
That may be another reason for the decrease in the enantio-
selectivity. Above all, the sulfonic, the primary amino and the
sulfonamido groups exhibited important impacts on both the
conversion of β-nitrostyrene and the enantioselectivity of the
Michael adduct.
The asymmetric Michael addition of aldehydes or
ketones to nitroolefins over IJ1R,2R)-IJ+)-1,2-DPEN-modified
sulfonic acid resin in a fixed-bed reactor was investigated.
As shown in Table 4, the Michael addition of acetone to
nitroolefins gave the desired adducts with excellent enantio-
selectivity (>90%) and moderate to high nitroolefin conver-
sion (47.1% to 95.7%). The conversion of 4′-methoxy-β-
nitrostyrene (47.1%) was lower compared with that of other
nitroolefins due to the effect of the electron-donating group.
Furthermore, the Michael addition of aldehydes or ketones
to β-nitrostyrene was performed. Excellent β-nitrostyrene
conversion and Michael adduct enantioselectivity were
observed when cyclohexanone or n-butanal was employed.
By contrast, the Michael addition of cyclopentanone and
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